Detecting thermal discrepancies in vessel walls

ABSTRACT

An infrared, heat-sensing catheter particularly useful for identifying potentially fatal arterial plaques in patients with disease of the coronary or other arteries and its use are detailed. In one embodiment, an infrared fiberoptic system (with or without ultrasound) is employed at the tip of the catheter to locate inflamed, heat-producing, atherosclerotic plaque, which is at greater risk for rupture, fissure, or ulceration, and consequent thrombosis and occlusion of the artery. In another embodiment, a catheter with an infrared detector (with or without ultrasound) employed at its tip will likewise locate inflamed heat-producing atherosclerotic plaque. The devices and methods of the invention may be used to detect abscesses, infection, and cancerous regions by the heat such regions differentially display over the ambient temperature of immediately adjacent tissues. The methods and devices of the invention may also be used to detect regions of cooler than ambient tissue in a vessel or organ which indicate cell death, thrombosis, cell death, hemorrhage, calcium or cholesterol accumulations, or foreign materials.

CROSS-REFERENCE TO RELATED APLICATION

The present application claims the benefit of 35 U.S.C. 111(b)Provisional application Ser. No. 60/004,061 filed Sep. 20, 1995, andentitled Catheters and Methods Detecting Thermal Discrepancies in BloodVessels.

This invention was made with government support under Grant No. 91HL07awarded by the National Heart Lung and Blood Institute, giving thefederal government certain rights in the invention. In addition, theinvention described herein was made in the performance of work under aNTASA contract and is subject to the provisions of Section 305 of theNational Aeronautics and Space Act of 1958, Public Law 85-568 (72 Stat.435; 42 U.S.C. 2457).

BACKGROUND OF THE INVENTION

A. Field of the Invention

This invention relates to the medical diagnosis and treatment ofarterial disease by means of temperature differential sensing, andparticularly, infrared-sensing with devices such as temperature probes,cameras, and catheters. In particular, the invention provides cathetersand methods of using catheters to diagnose arterial diseases detectableby thermal discrepancies in the arterial wall.

B. Description of the Related Art

Problems in Diagnosis

Plaque Physiology

Atherosclerotic coronary artery disease is the leading cause of death inindustrialized countries. An atherosclerotic plaque is a thickened areain the wall of an artery. Typically, patients who have died of coronarydisease may exhibit as many as several dozen atherosclerotic plaques;however, in most instances of myocardial infarction, cardiac arrest, orstroke, it is found that only one of these potential obstructions has,in fact, ruptured, fissured, or ulcerated. The rupture, fissure, orulcer causes a large thrombus (blood clot) to form on the inside of theartery, which may completely occlude the flow of blood through theartery, thereby injuring the heart or brain. A major prognostic anddiagnostic dilemma for the cardiologist is how to predict which plaqueis about to rupture.

Most ruptured plaques are characterized by a large pool of cholesterolor necrotic debris and a thin fibrous cap with a dense infiltration ofmacrophages. The release of matrix-digesting enzymes by the cells isthought to contribute to plaque rupture. Other thromboses are found onnon-ruptured but inflamed plaque surfaces.

Inflammation in an arterial plaque is the result of a series ofbiochemical and mechanical changes in the arterial wall. Plaque, athickening in the arterial vessel wall results from the accumulation ofcholesterol, proliferation of smooth muscle cells, secretion of acoliagmous extracellular matrix by the cells, and accumulation ofmacrophages and, eventually, hemorrhage (bleeding), thrombosis(clotting) and calcification. The consensus theory is thatatherosclerotic plaque develops as a result of irritation or biochemicaldamage of the endothelial cells.

The endothelial cells which line the interior of the vessel preventinappropriate formation of blood clots and, inhibit contraction andproliferation of the underlying smooth muscle cells. Most investigatorsbelieve that atherosclerotic plaques can develop when endothelial cellsare damaged or dysfunctional. Dysfunction in endethelial cells istypically produced as a result of injury by cigarette smoke, high serumcholesterol (especially oxidized low density lipoprotein), hemodynamicalterations (such as those found at vessel branch points), some viruses(herpes simplex, cytomegalovirus) or bacteria (e.g., Chlamydia),hypertension, some hormonal factors in the plasma (includingangiotensisn II, norepinephrine), and other factors as yet unknown. As aresult of these gradual injuries to the endothelial cells, anatherosclerotic plaque may grow slowly over many years. However, it isnow well documented that if a plaque ruptures, it often grows abruptly.

When plaque rupture develops, there is hemorrhage into the plaquethrough the fissure where the surface of the plaque meets thebloodstream. Blood coagulates (forms a thrombus) quickly upon contactwith the collagen and lipid of the plaque. This blood clot may then growto completely occlude the vessel or it may remain only partiallyocclusive. In the latter case, the new clot quite commonly becomesincorporated into the wall of the plaque, creating a larger plaque.

Plaques At Risk of Rupturing

Considerable evidence indicates that plaque rupture triggers 60% to 70%of fatal myocardial infarctions and that monocyte-macrophages contributeto rupture by releasing metalloproteinases (e.g., collagenases,stromelysin) which can degrade and thereby weaken the overly fibrouscap. Van der Wal, et al., Circulation 89:36-44 (1994); Nikkari, et al.,Circulation 92:1393-1398 (1995); Falk, et al., Circulation 92:2033-20335(1995); Shah, et al., Circulation 244 (1995); Davies, et al., Br Heart J53:363-373 (1985); Constantinides, J Atheroscler Res 6:1-17 (1966). Inanother 25% to 30% of faal infarctions, the plaque does not rupture, butbeneath the thrombus the endothelium is replaced by monocytes andinflammatory cells. Van der Wal, et al., Circulation 89:36-44 (1994);Farb, et al., Circulation 92:1701-1709 (1995). These cells may bothrespond to and aggravate intimal injury, promoting thrombosis andvasoconstriction. Baju, et al., Circulation 89:503-505 (1994).

Unfortunately, neither plaque rupture nor plaque erosion is predicableby clinical means. Soluble markers (P-selectin, von Willebrand factor,angiotensen-inverting enzyme, C-reactive protein, D-dimer; Ikeda, etal., Circulation 92:1693-1696 (1995); Merlini, et al., Circulation90:61-8 (1994); Berk, et al., Am J Cardiol 65:168-172 (1990)) andactivated circulating inflammatory cells are found in patients withunstable angina pectoris, but it is not yet known whether thesesubstances predict infarction or death. Mazzone, et al., Circulation88:358-363 (1993). It is known, however, that the presence of suchsubstances cannot be used to locate the involved lesion.

Low-shear regions opposite flow dividers are more likely to developatherosclerosis, (Ku, et al., Arteriosclerosis 5:292-302 (1985)), butmost patients who develop acute myocardial infarction or sudden cardiacdeath have not had prior symptoms, much less an angiogram. Farb, et al.,Circulation 92:1701-1709 (1995).

Certain angiographic data has revealed that an irregular plaque profileis a fairly specific, though insensitive, indicator of thrombosis.Kaski, et al., Circulation 92:2058-2065 (1995). These stenoses arelikely to progress to complete occlusion, while less severe stenoses areequally likely to progress, but less often to the point of completeocclusion. Aldeman, et al., J Am Coll Cardiol 22:1141-1154 (1993).However, because hemodynamically nonsignificant stenoses more numerousthan critical stenoses and have not triggered collateral development,those which do abruptly occlude actually account for most myocardialinfarctions. Ambrose, et al., J Am Coll Cardiol 12:56-62 (1988); Little,et al., Circulation 78:1157-1166 (1988).

Moreover, in postmortem studies, most occlusive thrombi are found over aruptured or ulcerated plaque that is estimated to have produced astenosis of less than 50% in diameter. Shah, et al., Circulation 244(1995). Such stenoses are not likely to cause angina or a positivetreadmill test. (In fact, most patients who die of myocardial infarctiondo not have three-vessel disease or severe left ventriculardysfunction.) Farb, et al., Circulation 92:1701-1709 (1995).

In the vast majority of plaques causing a stenosis less than or equal to50%, the surface outline is uniform, but the deep structure is highlyvariable and does not correlate directly with either the size of theplaque or the severity of the stenosis. Pasterkamp, et al., Circulation91:1444-1449 (1995); Mann and Davies Circulation 94:928-931 (1996).

Certain studies have been conducted to determine the ability to identifyplaques likely to rupture using intracoronary ultrasound. It is knownthat (1) angiography underestimates the extent of coronaryatherosclerosis, (2) high echo-density usually indicates dense fibroustissue, (3) low echo-density is a feature of hemorrhage, thrombosis, orcholesterol, and (4) shadowing indicates calcification. Yock, et al.,Cardio 11-14 (1994); McPerhson, et al., N Engl J Med 316:304-309 (1987).However, recent studies indicate that intra-vascular ultrasoundtechnology currently cannot discriminate between table and unstableplaque. De Feyter, et al., Circulation 92:1408-1413 (1995).

The rupture process is not completely understood, but it is known thatthe plaques most likely to rupture are those that have both a thincollagen cap (fibrous scar) and a point of physical weakness in theunderlying plaque. It is known that plaques with inflamed surfaces or ahigh density of activated macrophages and a thin overlying cap are atrisk of thrombosis. Van der Wal, et al., Circulation 89:36-44 (1994);Shah, et al., Circulation 244 (1995); Davies, et al., Br. Heart J53:363-373 (1985); Farb, et al., Circulation 92:1701-1709 (1995); VanDamme, et al., Cardiovasc Pathol 3:9-17 (1994). Such points are thoughtto be located (as determined by modeling studies and pathologicanalysis) at junctures where pools of cholesterol meet a more cellularand fibrous part of the plaque. Typically, macrophages (inflammatorycells), which produce heat, have been found at these junctures. Sincethese inflammatory cells release enzymes capable of degrading thecollagen and other components of the extracellular matrix, it is thoughtthat they are crucial to the process of plaque rupture or fissuring.

Transplant Vasculopathy

Inflammation also plays an important role in the rejection oftransplanted organs, a process which begins by an attack of host Tlymphocytes in the grafted donor organ's endothelial cells. Yeung et al.J. Heart Lung Transplant. 14:S215-220 (1995); Pucci et al. J. HeartTransplant. 9:339-45 (1990); Crisp et al. J. Heart Lung Transplant.13:1381-1392 (1994). Recruitment and proliferation of inflammatory andsmooth muscle cells are heat-generating processes, whose effects aredetectable in adamance of the detection of vessel narrowing using stresstests, ultrasound, or angiography. Johnson et al. J. Am. Coll. Cardiol.17: 449-57 (191); St. Goar et al. Circulation 85:979-987 (1992). Inaddition to the host attack of “non-self” antigens of the donor organs,many transplanted tissues develop cytomegalovirus infections, an eventthat is also heat-generating. Grattan et al. JAMA 261:3561-3566 (1989).These events in transplant physiology are ones for which it would bevaluable to track in patients recovering from such surgery.

Restenosis

Another serious problem in diagnostic cardiology is restenosis, arenarrowing of an artery that has undergone one or more interventionaltechniques to relieve an original stenosis (caused by plaque). Suchtechniques include balloon angioplasty, atherectomy (shanking or cuttingthe plaque), and laser angioplasty. Balloon angioplas of the coronaryarteries is a major advance in treatment and has been performed onhemodynamically significant coronary stenoses (those that are 70% to 99%of the cross-sectional diameter of thevessel) with a success rate of90%. In about 40% of the patients, however, restenosis occurs in thevessel and most of the benefit gained by the procedure is lost. Thus,another major diagnostic and prognostic dilemma for cardiologists notreadily addressed by prior art devices or methods is predicting whichpatients will develop restenosis.

Restenosis may occur when the removal of plaque by angioplasty oratherectomy injures the artery wall. The injury to the vessel wallcauses the smooth muscle cells at that site to proliferate and tosecrete an extracellular matrix which again narrows the artery. Bothcell proliferation and secretion are exergonic (heat-generating)processes. Additionally, it is known that macrophage concentration in avessel is correlated to the risk of restenosis.

Many factors have been reported to predict which patients will developrestenosis. However; these studies are markedly at odds with each otherand no factor has been strongly predictive of the restenosis process.Thus, cigarette smoking, hypertension, hypercholesterolemia, unstableangina, age. sex and many other factors have been only weaklypredictive, at best.

Prior Art Devices/Methods

A number of approaches and devices have been proposed to diagnose ortreat vascular obstructions. U.S. Pat. No. 3,866,599 relates to afiberoptic catheter for insertion into the cardiovascular system for themeasurement of oxygen in blood. For the purpose of detecting oxygenationlevels in the blood, optical fibers are used to first project infra-redand red light at the catheter tip into the blood. The infra-red and redlight reflected by the blood is then returned through the optical fibersto an oximeter. The ratio of infra-red light reflected to that absorbedby the blood is proportional to the oxygen saturation in the blood. Thiscatheter design is also one wherein there is at the distal end of theelement a recess preventing the ends of the fibers from contacting thevessel wall and an exterior sleeve which can be expanded to furtherspace the fibers from the wall of that vessel. However, the fiberopticcatheter of this patent does not permit detection of heat.

In some prior art devices, temperature sensing elements have been used.U.S. Pat. No. 4,752,141 relates to fiberoptic sensing of temperatureand/or other physical parameters using a system comprising (1) anoptical fiber (2) means including a source of visible or near visibleelectromagnetic radiation pulses at one end of the fiber for directingthe radiation along the fiber to another end of the fiber (3) a sensorpositioned at or near the end of the fiber in a manner to receive theradiation, modulate it by the temperature, and redirect the modulatedradiation back through the optical fiber to the sensor (4) the sensorcomprising at least one optical element in the path of the source ofradiation whose optical properties vary in response to the magnitude oftemperature changes and (5) means positioned at the end of the fiberreceiving the modulated radiation for measuring a function related tothe time of the resulting luminescent radiation intensity decay after anexcitation pulse indicating the temperature of the sensor. Thesetemperature sensors were designed to physically contact a surface andwere built with an elastomeric substance at the end of the fiber towhich a thin layer of phosphor material had been deposited. The phosphorreacts to the temperature and emits radiation which travels up the fiberand is detected by the sensor. Contact temperature determinationsrequire the ability of the catheter to be placed in contact with thelocus whose temperature is to be measured.

U.S. Pat. No. 4,986,671 relates to a fiber optic probe with a singlesensor formed by a elastomeric lens coated with a light reflective andtemperature dependent material over which is coated a layer of materialthat is absorptive of infrared radiation thereby allowing adetermination of characteristics of heat or heat transfer. Oneapplication is in a catheter for providing pressure, flow andtemperature of the blood in a blood vessel.

Other methods utilizing differing means for heat detection are known.The sensitivity and/or toxicity of these devices is unknown. U.S. Pat.No. 4,140,393 relates to the use of birefringement material as atemperature probe. U.S. Pat. No. 4,136,566 suggests the use of thetemperature dependent light absorption characteristics of galliumarsenide for a temperature sensor. U.S. Pat. No. 4,179,927 relates to agaseous material having a temperature dependent light absorption.

Other approaches utilize excitation techniques to detect heat. U.S. Pat.No. 4,075,493 relates to the use of a luminescent material as atemperature sensor, exciting radiation of one wavelength range beingpassed along the optical fiber from the measuring instrument, andtemperature dependent luminescent radiation being emitted from thesensor back along the communicating optical fiber for detection andmeasurement by the instrument. It is the luminescent sensor technologywhich has found the greatest commercial applicability in fiber opticmeasurements, primarily for reasons of stability, wide temperaturerange, ability to minimize the effect of non-temperature lightvariations, small sensor size and the like.

An example of a luminescent fiberoptic probe that can be used to measurethe velocity of fluid flow, among other related parameters, is given inU.S. Pat. No. 4,621,929. Infrared radiation is directed to the sensoralong the optical fiber and is absorbed by a layer of material providedfor that purpose. Once heated, the sensor is then allowed to be cooledby a flow of fluid, such cooling being measured by the luminescentsensor. The rate of cooling is proportional to the heat transfercharacteristics and flow of the surrounding liquid.

U.S. Pat. No. 4,995,398 relates to the use of thermography during thecourse of by-pass heart surgery for the purpose of checking the successof the operation before closing the chest cavity. This patent describesthe use of a scanning thermal camera, image processing, temperaturedifferentials and displaying images in real time. The invention relieson the use of a cold injectate which when it mixes with warmer bloodprovides images captured on a thermal camera focusing on the heart todetect stenoses at the sit of distal anastomcses.

U.S. Pat. No. 5,646,501 relates to a method of identifyingatherosclerotic plaque versus structurally viable tissues using afluorescent beam at a single excitation wavelength of between 350 and390 nm preferably from a laser which allows differentiation of thesetissues. No catheter was used in the examples of the patent. Thus, insitu imaging is not disclosed or taught by this patent. Moreover, notechnique is described by this patent for predicting plaque rupture,restenosis or transplant vasculopathy.

U.S. Pat. No. 5,057,105 relates to a hot tip catheter assemblycomprising a heater, a cap, a thermocouple, power leads, and a centraldistal lumen to position the catheter in the artery. The thermocouple isincluded to continuously monitor the heating of the catheter tip inorder to prevent overheating. The tip when properly placed on a plaquebuild up, melts the plaque.

U.S. Pat. No. 5,109,859 relates to ultrasound guided laser angioplastycomprising a laser at the tip of a catheter, an ultrasound device alsoat the tip of the laser for guidance, and a proximal occlusion balloonto provide stabilization and a blood free environment. This patentapparently also relates to estimating the mass of a plaque tissue. Thereis no teaching that the ultrasound device of the patent can distinguishhistological features (i.e., what cells and extracellular matrix arewithin the plaque). Thus, it is not likely that such a device could beused to predict plaque rupture. Indeed, recent studies have found thatintravascular ultrasound cannot identify which plaques are at risk ofrupturing. de Feytia Circulation 92:1408-13 (1995).

U.S. Pat. No. 5,217,456 relates to an intra-vascularguidewire-compatible catheter which has a source of illumination and asynchronous fluorescence detector. Light in a wavelength that inducesfluorescence in tissues emanates radially from an aperture on the sideof the catheter. Fluorescence emitted from the tissues enters thecatheter through the same aperture and is conveyed to a spectralanalyzer. This information can be used to differentiate healthy tissuefrom atherosclerotic plaque. However, this device does not distinguishbetween plaque on the basis of heat differential.

U.S. Pat. No. 5,275,594 relates to methods and apparatus fordistinguishing between atherosclerotic plaque and normal tissue byanalyzing photoemissions from a target site, The system includes asource of laser energy for stimulation of fluorescence by non-calcifiedversus calcified atherosclerotic plaque, and an analyzing means fordetermining whether a spectrum of fluorescence emitted by a tissuerepresents calcified or non-calcified atherosclerotic plaque at a targetsite, based upon the time domain signal of calcium photoemissionfollowing fluorescent excitation of the calcium. When atheroscleroticplaque is identified, laser energy is used to ablate the plaque.

Prior art approaches to intravascular arterial diagnosis and repair havebeen numerous yet have failed to provide certain capabilities. Inparticular, such prior art catheters and methods have failed to providemeans for detecting and treating atherosclerotic plaque since they havenot been able to differentiate between those plaques at risk ofrupturing and occluding and those that are not presently at such riskeven it they are capable of determining the presence or absence ofcalcification of the plaque. Similarly, prior art approaches have notprovided effective means for identifying specific arterial sites at riskfor arterial restenosis after angioplasty or atherectomy. Prior artapproaches have also failed to provide practical and effective means fordetecting transplant vasculopathy. Neither have prior art approachesbeen able to effectively identify patients who have arterial wall areasof lower rather than higher temperature, such as areas of extensivescarring, lipid pools where there is no cellular infiltration, or areasof hemorrhage and thrombosis which have yet to be colonized byinflammatory cells.

SUMMARY OF THE INVENTION

The present invention overcomes at least some of the failures of theprior art by providing an infrared-sensing catheter for detectingheat-producing inflammatory cells and vessel wall cells, and thuspredicting the behavior of injured blood vessels in medical patients.The catheters and methods of the present invention provide effectivemeans for detecting and treating atherosclerotic plaque which is capableof differentiating between, among other pathologies, those plaques atrisk of rupturing and occluding and those that are not presently atrisk. The catheters and methods of the present invention also provideeffective means for identifying specific arterial sites at risk forarterial restenosis after angioplasty or atherectomy, or which patientsare at risk due to vasculopathy, or tissue rejection. The catheters andmethods of the present invention also are capable of effectivelyidentifying patients who have arterial wall areas of unusually lowtemperature and which represent previously undetected arterial at-riskareas—just as excess heat can identify regions at risk due toinflammation, sub-normal heat (areas cooler than the rest of a vessel)indicates a lack of actively metabolizing healthy cells (since heat inthe body results from actively metabolizing cells). Non-cellular areasare typically regions of hemorrhage, thrombosis, cholesterol pools, orcalcium—all indicators of high risk plaques. The invention's devices andmethods achieve these ends by identifying and analyzing thermaldiscrepancies in the wall temperature of blood vessels.

The invention in one regard relates to apparatus for analyzing opticalradiation of a vessel. In another regard, the invention relates tomethods for analyzing optical radiation, which methods are bestpreferably achieved using the appartus of the invention.

Optical radiation of particular interest in the invention is thatradiation which falls in the optical spectrum in the wavelength intervalfrom about 2-14 μm. An attractive feature of infrared is its penetrationthrough calcium (relative to white light and ultrasound). Benaron, etal., J Clin Monit 11:109-117 (1995).

The vessels of particular interest in the invention are those vesselswhere the access to a surface of which is problematic. Thus, where theinternal diameter of a vessel is too small for ready access by atraditional temperature probe (i.e., a contact thermometer orthermocouple), the apparatus and methods of the invention will findutility. Similarly where the vessel, while of sufficiently largeinternal diameter for access by a temperature probe, has one or othersof its openings narrowed, occluded or otherwise blocked, the apparatusand methods of the invention will find utility. Thus, of particularinterest in application of the apparatus and methods of the inventionare vessels of the body, including vessels circulating and transportingsera (i.e. blood) such as arteries, veins, sinuses, heart cavities andchambers.

The invention relates to apparatus and methods in which there is atleast one optical fiber used which is capable of transmitting opticalradiation from a distal end of the fiber, usually inside a vessel, to aproximal end of the fiber, usually outside the vessel. Optical fibers ofthe invention will exhibit certain key parameters related to theirability to transmit wavelengths in the region of 2-14 μm. These keyparameters include optical transparency, flexibility and strength. Theoptical fibers of the invention are those which may be extruded inultrathin diameters and which transmit over the appropriate infra-redspectral region. The infrared fiberoptic can be constructed from avariety of substances known to those of skill in the art such aszirconium fluoride (ZrF₄), silica, or chalcogenide (AsSeTe). ZrF₄ fibersare well suited to the apparatus and methods of the invention becausesuch fibers have >90% transmission capabilities over 1 meter for smalldiameters.

The optical fibers useful in the apparatus and methods of the inventionwill also be ones capable of placement proximate to a locus of a wall ofthe vessel being investigated. This criterion is achieved in part by theflexibility of the fiber optic. In additional part, this criterion ismet by the ultrathin nature of the diameter of the fiber optic.

The apparatus and methods of the invention also utilize a balloon whichencases a distal end of the fiber. The balloon, in one embodiment, maybe one which is transparent to the optical radiation of interest. Inthat instance, optical radiation originating outside the balloon istransmitted through the outer surface of the balloon to the innersurface of the balloon and on to the entry point for optical radiationinto the optical fiber. It is important, in this embodiment, for thereto be little if any absorption, reflection or other diversion of theoptical radiation emanating from the source (i.e., the vessel wall, alocus such as a plaque locus) during its transmission through thesurfaces of the balloon. Such unwanted absorption may be caused by bloodor other body fluids. Therefore, transparency for purposes of theinvention means an ability to transmit substantially all opticalradiation from a particular source through the balloon surfaces to theoptical fiber.

It is important, in this embodiment, for there to be substantially totalconduction of the heat, while having substantially no loss of the heatemanating from the source (i.e., the vessel wall, a locus such as aplaque locus) as it contacts the outer surface of the balloon.Therefore, opacity (opaque) for purposes of the invention means anability to absorb substantially all optical radiation from a particularsource on the outer balloon surface. Thereafter, the inner surface ofdie balloon will re-emit a proportional amount of radiation to thatabsorbed on the outer surface immediately adjacent the locus originatingthe radiation. This re-emitted radiation will be detectable by the fiberoptic system encased inside the balloon.

The apparatus and methods of the invention also utilize a detectorcapable of detecting a difference in the optical radiation of interest,between the locus and the average optical radiation along the vesselwall being investigated. In certain preferred embodiments, the detectorof the invention is one which has a sensitivity capable of detection ofdifferences in infra-red radiation as small as 50 °mK, and in the rangeof 10 to 100 °mK.

Where the balloon is one which is transparent to the radiation directlyemitted from the locus or from the vessel wall portions outside thespecific locus, the detector will be one capable of detecting theradiation which is transmitted through the balloon's outer and innersurfaces. Where the balloon is one which is opaque to the radiationdirectly emitted from the locus or from the vessel wall portions outsidethe specific locus, the detector will be one capable of detecting theradiation which is reemitted from the balloon's inner surface oppositethe balloon's outer surface which is directly in contact with the locus.

In preferred embodiments the apparatus and methods of the invention willrely on detection of optical radiation in the infra-red radiationranges. In particular, as noted above, ranges of 2-14 micrometers are ofparticular interest in the apparatus and methods of the invention.Referring to FIG. 2, it can be seen that it is possible to plot curvesfor radiation (numbers of photons×1×10¹⁷) being emitted by black bodiesheld at differing constant temperatures (T₁, T₂ and T₃ each refer totemperatures in the range of 300-310° K. which vary from one anotherincreasingly by 1° K.) in the wavelength range of 3 up to 6 micrometers.It can also be seen in the inset to FIG. 2, that in the range ofapproximately 5.3 to 5.6 micrometers, black bodies held at constanttemperatures in the range of 300-310° K. and differing from one anotherby only a single degree, appear as easily distinguishable curvesegments, emitting photons from these black bodies in the range ofapproximately 0.21×10¹⁷ to 0.40×10¹⁷ photons. Thus, it is preferred toselect a wavelength for sampling the radiation from the wall andspecific locus on the wall of a vessel which will provide similarlydistinguishable curves.

In certain preferred embodiments, the apparatus and methods of theinvention may comprise at least two fibers, although the use of greaterthan two fibers is clearly possible where merited, such as whendetection along the axis of the vessel is preferred at greater than asingle position simultaneously. In other preferred embodiments, where atleast two fibers are utilized, at least one of the fibers is a referencefiber and another of the fibers is a signal fiber. The signal fiber is afiber designed to transmit all optical radiation focused into its lengthfrom its distal end to its proximal end. Conversely, the reference fiberis a fiber which is used as a control against which the signal fibertransmissions may be compared. Thus, where optical radiation exiting theproximal end of the signal fiber is compared to that exiting theproximal end of the reference fiber, a determination can be readily madeas to relative amounts of optical radiation exiting the signal fiberwhich is due to other than optical radiation emitted by the locus ofinterest.

The apparatus of the invention may also be optically connected at thedistal end of the signal fiber to an optically reflective surfacecapable of directing optical radiation arising radially to said distalend, and on into said fiber. U.S. patent application Ser. No. 08/434,477in which certain of the present inventors are named co-inventors, andwhich is incorporated herein by reference, describes such an opticallyreflective surface. As opposed to the signal fiber, the reference fiberwill typically be coated on its distal end with a material thatsubstantially prevents optical radiation from entering it.

The apparatus of the invention is also one in which the inner surface ofthe opaque occluding balloon emits a black body spectrum modulated bythe transmission spectrum of the balloon. The balloon, upon inflation,will substantially limit flow of fluids within the vessel. The flowlimitation required is one in which only so much flow occurs as will notcause a rise or fall in average background IR radiation along the vesselwall immediately distal the inflated balloon. In addition, in preferredembodiments, the apparatus of the invention is one where the balloon,upon inflation, substantially excludes the presence of intervesicularfluids between the fibers inside the balloon and the wall of the vesselmost proximate to the test locus.

In use, the apparatus of the invention will be placed along an axis ofthe vessel. in this manner, it will be possible to bring the diagnosticfiber array into close proximity with a locus to be diagnosed. Incertain preferred embodiments, the locus will be one which containsplaque. In particular, the apparatus as previously noted will be usefulin detecting among those plaques with which it is brought intoproximity, whether a given plaque is one at risk of rupturing. In mostinstances, the apparatus of the invention will be used to diagnosethermal discrepancies on the interior wall of a vessel.

The apparatus of the invention is in its most preferred embodiments acatheter. Typical of catheters used inside of blood vessels, thecatheter of the invention will be one designed for use with a guidewire.The guidewire will allow optional removal and reinsertion at thediscretion of the surgeon, for example where after diagnosing a plaqueat risk of rupturing using the catheter of the invention, the surgeonmay wish to bring another diagnostic device or a therapeutic device suchas a laser into the same position next to the problematic plaque.

The apparatus of the invention is also one where the detector ispreferably optically connected to a proximal end of the fiber, and ifthere is more than one fiber, to a proximal end of each of the fibers.In preferred embodiments, the detector will be a multi-wavelengthradiometer.

Such a radiometer will preferably be a spinning circular variable filterwhose transmission wavelength is a function of its angle of rotation. Insuch a filter, it is possible to prevent transmission of all but anarrow band of wavelengths of light by adjusting the rotational angle.Said differently, such a filter can be made to be transparent to highlyselected wavelengths by its rotational characteristics. Thus, in certainembodiments, the filter will be one transparent to radiation with awavelength of approximately between 2 to 6 micrometers. In highlypreferred embodiments, the filter will be transparent to radiation witha wavelength of approximately 3 micrometers.

One of the keys to this invention as it relates to the apparatus, isthat it automatically provides a reference for each spectrum by samplingapproximately 3 μm. For the range of temperatures expected in biologicalorganisms, 300-310° K., the blackbody spectrum at this wavelength isessentially the same. This provides a zero for each signal and locksdown the low wavelength side of the signal. Without this, there would beno way to fit a signal to a blackbody spectrum since the vertical scalewould be “unfixed”.

Where the apparatus of the invention utilizes the transmittedinformation from more than one fiber through a filter for comparativepurposes, it will be preferred to utilize an offset in the distal fiberends. Thus, where the distal ends of the signal fiber and the referencefiber are offset from one another, the offset will be at a distancesufficient to allow sampling of radiation emitted from either fiber topass the filter at a substantially identical location on the filter.

The apparatus of the invention when used in conjunction with aradiometer, will preferably be one optically connected to at least onephotoelectric device capable of converting the transmitted radiationinto an electrical signal. The photoelectric device is preferably oneelectrically connected to a device capable of digitizing the electricalsignal (a digitizer).

Once the apparatus of the invention has created a digitized signal, thedigitized signal is mathematically fitted to a curve selected from aspectrum of curves for black bodies held at temperatures betweenapproximately 300-310° K. The curves of the controlled black bodies arethose plotted as numbers of photons emitted from each black body foreach wavelengths. In instances where such a digitized signal is to beused to diagnose thermal discrepancies in the interior wall of a bloodvessel, the particular selection of black body control curves will bemade with the knowledge of typical temperatures of the human body.

Thus, in a preferred embodiment, the apparatus of the invention will bea catheter for analyzing infra-red radiation of a blood vessel. Such apreferred device will comprise at least two fibers capable oftransmitting the radiation and capable of placement along an axis of thevessel proximate to a plaque containing locus of an interior wall of thevessel. At least one of the fibers will be a reference fiber coated onits distal end with a material that substantially prevents opticalradiation from entering it, and at least one of the other of the fiberswill be a signal fiber whose distal end is optically connected to anoptically reflective surface capable of directing optical radiationarising radially to its distal end into and along its shaft. Such apreferred device will also have a balloon encasing the distal ends ofeach of the fibers, which balloon upon inflation will substantiallylimit the flow of fluids within the blood vessel. In addition, theballoon will substantially exclude fluids between the fibers and thewall of the vessel most proximate to the locus to be tested. The balloonwill be transparent to or opaque to the radiation arising inside thevessel and will have an inner surface exhibiting spatially constantoptical radiation emissivity. This inner surface of the opaque balloonwill be one which emits a black body spectrum. The catheter will be onehaving a guidewire. It will also have a detector, optically connected toa proximal end of each of the fibers, and capable of detecting adifference in the radiation between the locus and average opticalradiation along the wall of the vessel. The detector will furthercomprise a multi-wavelength radiometer with a spinning circular variablefilter, the filter being such that its transmission wavelength is afunction of its angle of rotation. The distal ends of the fibers will beoffset from one another a distance sufficient to allow sampling ofradiation emitted from either fiber to pass the filter at asubstantially identical position on the filter. Further, the radiometerwill be optically connected to at least one photoelectric device capableof converting the transmitted and filtered radiation into an electricalsignal, which signal is capable of being digitized, and which digitizedsignal is mathematically fitted to a curve selected from a spectrum ofcurves for black bodies held at temperatures between approximately300-310° K., where the curves are plotted as numbers of photons emittedfrom each of the black bodies for each of the wavelengths.

The invention also relates to an analytical method, suitable in certainembodiments for diagnosing medical conditions. Thus, the inventionrelates to a method for analyzing optical radiation of a locus in avessel wall. The method of the invention comprises placing at least oneoptical fiber capable of transmitting radiation proximate to the locus.In preferred embodiments, the placement of the fiber and balloon isaccomplished by catheterization. Either prior to or after placementproximate to the locus to be analyzed a balloon encasing a distal end ofthe is fiber is inflated within the vessel to cause the balloon to limitflow of fluids within the vessel. As previously detailed, the balloon istransparent to or opaque to the thermal radiation and has an innersurface exhibiting spatially constant optical radiation emissivity. Themethods of the invention further call for transmitting the radiationalong the fiber to a detector capable of detecting a difference in theradiation between the locus and the average optical radiation along thevessel wall.

More specifically, the invention relates to a method of detecting plaqueat risk of rupturing alone a blood vessel. This preferred methodcomprises inserting a guidewire into the blood vessel to be diagnosedand then catheterizing the vessel along the guidewire with at least twofibers capable of transmitting infra-red radiation along an axis of thevessel proximate to a plaque-containing locus of an interior wall of thevessel. Thereafter, the steps of the method of the invention is carriedout as described above.

The invention also relates to a method of surgically treating a patientwith a plurality of plaque loci within a vessel. Such a method comprisesdetermining which one or more of the plurality of plaque loci has atemperature elevated above that of the average vessel wall temperature.Once such a determination is made, the surgeon removes or reduces theplaque loci found to have an elevated temperature. This method has asits determination step the methods described above for analyzing opticalradiation of plaque locus in a vessel wall. Once plaque at risk isidentified, a number of therapies may be used to reduce the risk.

Accordingly, it is an object of the present invention to identifypatients who have coronary atherosclerotic plaque at risk of rupture byidentifying the specific plaque(s) at risk. Another object of thepresent invention is to identify patients at risk for arterialrestenosis after angioplasty or atherectomy by identifying the specificarterial site(s) at risk. A further object of the present invention isto identify patients at risk of transplant vasculopathy. Another objectis to identify patients at risk for stroke, loss of mobility, and otherillnesses by identifying sites of potential plaque rupture in thecarotid arteries, the intracerebral arteries, the aorta, and the iliacand femoral arteries. Another object of the present invention is toidentify patients who have arterial areas of lower rather than highertemperature, such as an area of extensive scarring, a lipid pool with nocellular infiltration, or an area of hemorrhage and thrombosis which hasyet to be colonized by inflammatory cells. The delineation of acholesterol pool is useful in following the regression of plaques.Identifying such areas for follow-up study will localize those likely tobe inflamed in the future.

Yet another object of the present invention is to deliver specific localtherapy to the injured areas identified by the catheter. These therapiesinclude, but are not limited to, therapies which prevent or limitinflammation (recruitment, attachment, activation, and proliferation ofinflammatory cells), smooth muscle cell proliferation, or endothelialcell infection, including antibodies, transforming growth factor-β(TGF-β), nitric oxide (NO), NO synthase, glucocorticoids, interferongamma, and heparan and heparin sulfate proteoglycans, and the variouscomplementary DNAs that encode them.

The invention's methods and devices will have a number of utilities.Bach will reduce morbidity and mortality from coronary and carotidartery atherosclerosis. Each will reduce the incidence of restenosis andthus the need for repeated angioplasties or atherectomies. Each willalso reduce the incidence of vasculopathy in organ-transplant patients.In turn, these outcomes will produce the benefits of better health care,improved public health, and educed health care costs. These and otheruses of the present invention will become clearer with the detaileddescription to follow.

BRIEF DESCRIPTION OF THE DRAWINGS

FIG. 1 is a schematic representation of the apparatus of the presentinvention with its infra-red detection unit at its proximal end and thesensor tipped distal end of the catheter as well as the guide wiredisposed within a flexible outer catheter (not shown) which surroundsthe optical fibers.

FIG. 2 is a black body curve spectrum for temperatures T1, T2, and T3(differing sequentially by a single degree Kelvin) plotted as emittedradiation in photons (x1E17) versus wavelength (micrometers).

FIG. 3 is a length-wise cross sectional view of the catheter tip of FIG.1 in place within a blood vessel near a plaque at risk of rupture.

FIG. 4(a) is a graph depicting surface temperature of living carotidartery plaque in relation to cell density. Relative cell density equalsthe ratio of cell density in the area of interest to that of thebackground area. Temperature measurements were made at room temperature(20° C.) on 24 samples from 22 patients 10-15 minutes after removal.Point (O° C. difference in temperature) represents 27 observations.

FIG. 4(b) shows the correlation between living human carotid plaquetemperature and cell density when measured in a 37° C. chamber.

FIG. 5 is a graph depicting plaque surface temperature as a function ofcap thickness. Samples that had a non-inflamed fibrous cap weresubjected to planimetry to measure distance from the lumen to the centerof the underlying cell cluster.

FIG. 6 shows the correlation between thermistor and IR camerameasurements in living human carotid plaque specimens (freshly excised,in a 37° C. chamber) where r=0.9885 and p=0.0001.

FIG. 7 shows the correlation of IR radiation with cell density in thespecimens described in FIG. 6, above.

DESCRIPTION OF PREFERRED EMBODIMENTS The Catheter Embodiment

Referring now to the figures, FIG. 1 shows a preferred embodiment of theapparatus of the invention in use. A catheter apparatus 10 is shown,which can be placed inside an artery (not shown) having with an interiorarterial wall (not shown) which possesses a plurality of plaque loci(not shown). The risk; of rupture of either of the plaque loci isunknown until the methods and apparatus of the invention are applied.

Guidewire 20 has been surgically inserted into the artery and can beseen to extend both proximally 22 and distally 24. Guidewire 20 can alsobe seen to proceed through catheter apparatus 10. Guidewire 20 is usedto guide the placement of catheter apparatus 10 to the area of theartery which contains plaque loci.

Catheter apparatus 10 comprises at its distal end (the end farthest fromthe detector) an inflatable balloon 40, a signal fiber 50, and areference fiber 60. Inflatable balloon 40 is shown in its inflatedstate, which would cause it to rest firmly against an interior wall ofan artery and against plaque loci. Depending upon the natural directionof blood flow within the artery, inflation of balloon 40 wouldsubstantially limit flow of blood either at position 32 or 34 or any ofthe similar points around the perimeter of the generally circular seriesof contact points between the balloon wall 42 and an interior arterywall, allowing measurements being conducted by catheter apparatus 10 toproceed without interference.

Balloon 40 comprises a wall 42 which is made of an elastic material. Theperimeters of balloon 40 are such that inflation causes sealing orclosure of the balloon 40 at points along the arterial wall. Whendeflated, balloon 40 retreats from its contact of the arterial wall,allowing reestablishment of natural blood flow within the artery, andallowing facile movement of catheter apparatus 10 in the artery to anext position, for instance to a position at which catheter apparatus 10may be used to measure radiation emitted from another plaque locus.Activation of inflation/deflation of balloon 40 may be accomplished inany of a number of ways known well to those of skill in the art ofbuilding angioplasty or embolectomy catheters or balloon-tippedcatheters.

The purpose of balloon 40 is to avoid problems associated withabsorption of infra-red radiation by water between the source ofinfra-red radiation being measured and the distal catheter portion. Uponinflation and contact of the artery wall, the balloon wall 42 assumesthe temperature of the portions of the artery with which it is mostproximate. The void area 46 excludes all water between the balloon wallinterior and the distal signal fiber tip 56.

Signal fiber 50 has a translucent tip region 52 and an opaque bodyregion 54 which is capable or incapable, respectively, of transmittinginfra-red radiation efficiently. Opaque body region 54 may be a regionin which signal fiber 50 is covered over by a cladding or sleeve 56which causes the region to become opaque and incapable of efficientlytransmitting or absorbing infra-red radiation. Translucent region 52 maysimply be an area in which signal fiber 50 is exposed. Signal fiber 50is an optical fiber which can efficiently transmit infra-red radiation.In order to collect such radiation from the surrounding milieu, signalfiber 50 may be fitted or otherwise used at its distal end with acollecting device 58 which focuses the infra-red radiation of thesurrounding milieu into the fiber for subsequent transmission.

Unlike signal fiber 50, reference fiber 60 has no translucent region.Rather, reference fiber 60 has an opaque end 62 and an opaque region 64,both of which are incapable of transmitting infra-red radiationefficiently. As with the signal fiber 50, reference fiber 60, opaqueregion 64 may be a region in which reference fiber 60 is covered over bya cladding or sleeve 66 which causes the region to become opaque andincapable of efficiently transmitting or absorbing infra-red radiation.Opaque end 62 may be an area in which reference fiber 60 is coated withan infra-red reflective coating such as polished silver or aluminum. Inall other regards, reference fiber 60 is identical to signal fiber 50 inits ability to function as an optical fiber which can efficientlytransmit infra-red radiation. It may be used, therefore, to set abaseline in order to compensate for any temperature profile along signalfiber 50 from its distal to its proximal end. As shown in FIG. 1,reference fiber 60 is offset from signal fiber 50 in the proximaldirection. This offset (which can be equally well accomplished byoffsetting distally) physically introduces a time delay between theradiation received and transmitted by each fiber. As will be discussedimmediately below, this time delay is introduced in order to ensure thatthe signal and reference beams issuing from the proximal ends of eachfiber strike the filter on the same spatial portion. By doing so,it ispossible to eliminate alignment problems or bandpass dissimilaritesarising from a multi-filter system.

When in operation, the fiber-balloon array 70 collects thermal radiationwhich is transmitted proximally through signal fiber 50 and referencefiber 60. Both fibers are positioned to transmit through spinningradiometer 80 at identical radial position 82 to impinge on digitizers92 or 90, respectively. Once a digitized signal is generated from eachof the optical fiber transmissions, the background signal created by thereference fiber 60 is subtracted by computer 94 from the digitizedsignal transmitted by the signal fiber 50. The resulting adjusted signalis mathematically fitted by computer 94 to a spectrum of black bodycurves 96 in order to ascertain the temperature of the particular locus.

Catheter Construction

Several options for materials for the other various components of thecatheter devices described herein exist The key parameters for theoptical components are optical transparency, flexibility and strength.Materials such as high strength polyester and polyethylene terephthalate(PEI) are very clear and easily extruded in ultrathin wall sizes. A highstrength braided polyester is useful for translating twisting motionsover long distances as may be required in certain embodiments.Spacers/bearings can be made from Teflon®. The overall flexibility ofthe catheter will be approximately the same as similar-sizedcardiovascular laser, fiberoptic, angioplasty and atherectomizingcatheters. These devices should therefore be deliverable to smalldiameter coronary arteries. A detector will be positioned at theproximal end of the catheter (outside the patient) utilizing InSb or,alternatively, HgCdTe, TeO₂ or TAS detection systems.

The elongated flexible fiberoptic element will be connected at one endto an optical connector through a protective sheath. The opticalconnector is a standard item adapted to be slidably inserted into athermal detector, and will include a plurality of openings in one sidethrough which fluids or gases, including air, can be-introduced into thecatheter and emitted therefrom. The connector will also include acoupling element for connecting to a pressure transducer to measurepressure, there being an opening in the connector communicating with thecoupling element and the pressure lumen of the catheter. The couplingelement may also be connected to a syringe to take a blood sample or touse a saline solution to flush the catheter.

The materials of which catheters are constructed may be any of thosecommonly used, including flexible plastics such as nylon, Teflon™,vinyls such as polyvinyl chloride, polyurethane, and polyethylene, orvarious rubber compounds. Typically, the catheter will typically be 5 to40 inches long and have an outer diameter of about 1 to 2 millimeters.The lumen inside the catheter can vary but typically will be about onehalf to 1 millimeter in diameter.

The minimum detectible heat differential using the devices and materialsof the present invention will be about 0.1° C. While the devices of theinvention will be capable of finer thermal discrimination, biologicalvariables are apt to introduce noise into the system. In most instances,plaques which are in danger of rupturing will vary from those less atrisk by at least 1.5° C.

At-Risk Plaque

Generally then, as an overview of the device and method of the inventionin FIG. 3, the infrared-sensing catheter 100 has identified an ulceratedatherosclerotic plaque 102 which is accompanied by platelet aggregation103 and vasoconstriction 104 Because of the presence of inflammatorycells 105 in this plaque 102, its temperature is higher than that of theimmediately adjacent vessel 107, and this change is sensed by thecatheter 100. Some endothelial cells 108 have been lost (as a result ofsenescence, inflammation, infarction, toxins, or balloon injury) causingplatelets 109 to become activated and to adhere to the imaged vesselwall 110. The activated platelets 109 release mediators that causevasoconstriction, platelet aggregation, and growth of smooth musclecells; these mediators include ADP, serotonin, thromboxane A₂,platelet-derived growth factor, transforming growth factor-β, and PF4.The exposure of subendothelial collagen 111 and lipid 112 and theactivation of platelets promote enzymatic activation of coagulationenzymes, which result in the release of plasma mitogens and theactivation of thrombin, an enzyme which cleaves fibrinogen to formfibrin. The culmination of this process may be complete occlusion of theartery and consequent injury to the heart (or brain, in the case of acarotid, vertebral or cerebral artery).

Also shown is a monocyte 114, which has attached itself to adhesionmolecules on the surface of activated endothelial cells. The monocytebecomes a macrophage involved in uptake of modified cholesterol and therelease, as by-products, of mitogens and proteolytic enzymes that maypromote rupture.

EXAMPLE I

Methods

Fifty carotid endarterectomy specimens were studied in the living stateafter gross inspection by a pathologist. Visible thrombi, noted in about30% of the specimens, were typically removed by gentle irrigation,suggesting that they were surgical artifacts. The indications forsurgery were generally a carotid stenosis and transient ischemic attackor stroke.

Twenty-four specimens from 22 patients were examined at room temperature(20° C.). Another 26 specimens from 26 patients were examined in ahumidified incubator at 37° C.

Within 15 minutes after removal of a specimen, a Cole-Parmer model8402-20 thermistor with a 24-gauge needle tip (accuracy, 0.1° C.: timeconstant, 0.15) was used to measure the temperature of tile luminalsurface in 20 locations. Temperatures were reproducible (+0.1° C.), andmost measurements were found to be within 0.2° C. of each other and thuswere designated as the background temperature.

In most plaques, several locations with higher temperature were allfound. These locations and the background temperatures were marked withindelible ink of varying colors (recorded, but not coded so as toindicate the temperature to the pathologist) and re-measured to assurereproducibility. Tissues were then fixed in 10% formalin and cutlengthwise, embedded to reveal the intima and media, processed forhistology, and stained with hematoxylin and eosin or Masson's trichrome,or immunostained for macrophages using the HAM-56 and KP-1 antibodies(Dako) as previously described. Nikiri, et al, Circulation 92:1393-1398(1995). The cap thickness and the cell density in a 300×400-μm regionbeneath the dyed regions was measured using a Mackintosh Centris 650 andNIH Image software (version 1.43), available on the Internet from theNational Institutes of Health, Bethesda, Md.

Preliminary experiments were also performed with a Jet PropulsionLaboratory platinum silicide camera, which we further calibrated againsta Mach 5 scanning infrared camera (Flexitherm, Westbury, N.Y.),—which inturn was calibrated against beakers of water at various temperaturesfrom 0 to 100° C. with a near perfect correlation, y=0.99x+0.31, where xwas the temperature measured by mercury thermometer. The camera had athermal resolution of 0.10° C. and a spatial resolution of 0.15 mm.

Results

Plaques exhibited multiple regions in which surface temperatures variedreproducibly by 0.2 to 0.3° C. (±1.0° C.), and 37% of the plaques had 1to 5 substantially warmer (0.4 to 2.2° C.) regions per plaque. Forinstance, in typical instances, regions 1 mm apart had a reproducibletemperature difference of 0.6° C. Although the lumenal surfaces of theplaques exhibited visible heterogeneity, differences in temperature werenot apparent to the naked eye. These temperature differences correlatedpositively with the underlying density of cells (r=0.68, p=0.0001) (FIG.4A), most of which were mononuclear cells with the morphologiccharacteristics and immunoreactivity (with HAM-56 and KP-1) ofmacrophages.

Several mitotic figures were noted. Some foam cells were noted, butregions predominantly populated by foam cells were cooler (and had lowercell density) than regions with mononuclear infiltrates. Many plaquescontained a few lymphocytes and mast cells.

Temperature varied inversely with cap thickness (r=−0.38, p=0.0006)(FIG. 5). The best correlation (r=0.74, p=0.009) was given by thetheoretically expected equation ΔT=relative cell density÷cap thickness.Cooler regions were nonellular: fresh thromboses, hemorrhage, scar,calcium, or regions of cholesterol pooling without inflammatoryinfiltration.

The warmer regions were not visibly different on gross inspection, eventhough many of them had a superficial layer of inflammatory cells, someof which had small aggregations of platelets. Other large areas werefree of inflammatory cells but lacked endothelial cells. These hadprobably been denuded during surgery, since postmortem studies usuallyshow only focal denudation unless there is thrombosis or inflammation.Van Damme, et al., Cardiovasc Pathol 3:9-17 (1994).

A minority of plaques (approximately 20%) exhibited no detectablethermal heterogeneity. Regions of deep or superficial inflammation inthese specimens were not marked with dye, indicating that the overlyingtemperature had not been measured. In a few of the regions containingcellular infiltrates, temperatures had been measured, and they were nowarmer than less cellular adjacent areas. This finding was believed bythe inventors to possibly defect decayed metabolic activity in specimensthat were kept at room temperature for a longer interval after removal.

Therefore, a second series of plaques was analyzed in a 37° C.incubator. These 26 specimens from 26 patients with a mean age of 68(range, 50 to 86) revealed a considerably closer correlation with celldensity (r=0.68, p<0.0001), more thermal heterogeneity (93% ofspecimens), and a wider range of temperatures, typically 1 to 3° C.;some specimens only 10 mm apart were characterized by temperaturedifferences as great as 4 to 5° C. See, FIG. 4B (points represented bysolid diamonds are the relative cell densities divided by the capthickness squared; linear regression of these points resulted in thesolid line shown).

The inventors also studied several specimens using a platinum silicide,cooled, infrared camera with a thermal resolution of 0.1° C. and aspatial resolution of 0.1 mm. This camera detected thermal heterogeneityin ex vivo specimens. As shown in FIG. 6, the IR camera when used toidentify thermally distinct plaque correlated well with direct contactthermistor measurements in freshly excised human carotid artery plaquesspecimens (r=0.9885, p<0.0001). FIG. 7 shows that this correlation ofthe IR camera measured temperatures was also observed with cell densitymeasurements. It is noted by the inventors that cooled staring arraycameoas have even better thermal resolution, and spatial resolutions areas low as 10 μm.

Conclusions

Most human carotid atherectomy specimens contain foci of increased heatapparently produced by underlying cells, most of which are macrophages.When studied at 37° C., the temperature variation was greater than 20°C., consistent with reduced metabolic activity at 20° C. that makes theplaques more homogeneous in temperature.

In the samples studied at body temperature, a thermistor with a 1-mm tipwas able to detect differences as great as 4° C. within different partsof the same plaque that were only 10 mm apart. Temperatures were highestwhen the cells were closest to the probe (i.e., at or just beneath thelumen itself). Most of the lumenal surfaces of the plaques had severalregions characterized by superficial inflammation and endothelialdenudation.

Only some areas of surface inflammation were associated with visiblethrombosis; most were associated with microscopic thrombosis (e.g., afew fibrin strands and attached platelets) or nonlall. These resultssuggest that increased plaque heat is an indicator of plaques that aredenuded and inflamed and consequently at risk of thrombosis.

The inventors also found a few hot regions associated with foci ofinflammation just beneath thin but intact caps. Since these plaques arebelieved to be at increased risk of rupture, it is believed by theinventors that measuring plaque temperature in vivo could enable one toidentify such plaques.

EXAMPLE II

Limitations of the Study

A potential confounder identified by the inventors is plaqueangiogenesis (neovascularization). The inventors studied living plaquesex vivo. In vivo, the presence and tone of the vasae vasorum mightinfluence the temperature. However, since plaque angiogenesis coreuateswith inflammation, (Nikkari, et al., Circulation 92:1393-1398 (1995) andboth are considered risk factors for plaque rupture, it is likely thattemperature will still be predictive in vivo.

The inventors also believe that one must consider that what is true foratherosclerotic plaque in the carotid arteries may not be true in othersites, for example, the coronary arteries. The pathology of the plaqueis somewhat different in the two locations. (Van Damme, et al.,Cardiovasc Pathol 3:9-17 (1994)) and the risk factors are alsodifferent. Kannel, J Cardiovasc Risk 1:333-339 (1994); Sharrett, et al.,Arterioscler Thromb 14:1098-1104 (1994).

EXAMPLE III

Potential of Spectroscopy, Tomography, and Interferometry

Infrared spectroscopy could prove useful in several ways. First, itshould be able to corroborate the location of macrophages by the massiveamounts of nitric oxide they produce, since nitric oxide has acharacteristic near-infrared spectrum. Ohdan, et al., Transplantation57:1674-1677 (1994). Near-infrared imaging of cholesterol has alreadybeen demonstrated. Cassis, et al., Anal Chem 65:1247-1256 (1993).Second, since infrared and near-infrared wavelengths penetrate tissuemore deeply as wavelength increases, longer wavelengths should revealmetabolic activity in deeper (0.1- to 1-mm) regions.

This phenomenon could be used to develop computed infrared tomography,possibly in conjunction with interferometry, in which an incident beganis split by a moving mirror to produce a reference beam and a beam thatis variably scattered and absorbed by the tissue. The nonsynchronousreflected wavelengths are reconstituted to reveal structural detail with20-μm resolution. Benaron, et al., Science 259:1463-1466 (1993);Brezinski, et al., Circulation 92: 1-149 (1995).

EXAMPLE IV

Noninvasive Detection of Plaques at Risk

Alternatives to infrared detection are also desirable since infraredabsorption, convection, and tissue emissivity differences are likely topreclude non-invasive infrared tomography. Such alternatives includeimaging the inflammatory cells with gallium, (Pasterkamp, et al.,Circulation 91:1444-1449 (1995)) ¹⁸FDG positron scanning, radiolabeledanti-macrophage antibody fragments, or magnetic resonance (to takeadvantage of the temperature-dependence of proton-spin relaxation).MacFall, et al., Int J Hyperthermia 11:73-86 (1995).

These techniques lack sufficient spatial resolution for detectinginflammatory foci bent the surface of moving coronary arteries(particularly circumflex and distal vessels) and cannot be used ‘online’ to direct plaque-specific interventional therapies. However, theresolution in these techniques may be adequate in thick-walled,relatively stationary arteries such as the aorta, carotid and femoralarteries. Toussaint, et al., Arteriocler Thromb Vas Biol 15:1533-1542(1995); Skinner, et al., Nature Medicine 1:69 (1995). If lumenalinflammation can be distinguished from adventitial inflammation, thelatter may prove useful in predicting progression of aortic aneurysms.

EXAMPLE V

Therapeutic Implications

Lowering serum cholesterol concentrations by means of diet or drugs canreduce mortality, perhaps because reverse cholesterol transport reducesthe size of the lipid core. However, the most convincing trial to dateindicates only a 35% decrease in coronary mortality withcholesterol-lowering therapy (and little benefit in women). ScandinavianSimvastatin Survival Study Group, Lancet 344:1383-1389 (1994). Thisfinding suggests that other factors, such as hemostatic variables, areaffecting mortality. However, even with the same patient, plaquesprogress or regress relatively independently. Gould, Circulation90:1558-1571 (1994). This variability suggests that lesion-specificvariables (for example, stenosis length, surface thrombosis, low shearstress due to low or turbulent flow, and vasoconstriction) increase therisk of thrombosis. Alderman, et al., J Am Coll Cardiol 22:1141-1154(1993); Nobuyoshi, et la., J Am Coll Cardiol 18:904-910 (1991).

If hot plaques producing stenoses in the “non-critical’” range of 10% to70% are shown to be at high risk of rupture, should they undergoangioplasty? If the risk of dilation is similar to that of more severestenoses (approximately 1% mortality, 2% aortocoronary bypass), what isthe benefit of converting an unstable lesion into one with a 70% chanceof long-term patency and a 30% chance of restenosis? Even before therecent trials indicating that stents reduce restenosis rates to 10% to20%, the large Emory follow-up indicated an identical 96% five-yearurvival rate in patients with and without restenosis, despite theincreased need for repeat ngioplasty or bypass surgery in the formergroup. These data suggest that angioplasty could be beneficial if thenear-term risk of sudden (spontaneous) occlusion is only about 5%.

EXAMPLE VI

Medical Therapies

Medical therapies would depend, in part, on whether the inflammation ison the surface or beneath an intact cap. This distinction may one day bemade by angioscopy (especially with the use of light-emittingantibodies) or by sampling blood for soluble markers of inflammation(P-selectin, VCAM-1, and others). Magnetic resonance imaging,ultrasound, and near-infrared imaging may also prove helpful.

Therapies might include local delivery of agents (peptides, peptidemimetics, oligonucieotides, and others) that prevent monocyterecruitment, attachment, activation, or DNA synthesis. Conversely,Collagen synthesis might be stimulated with ascorbic acid ortransforming growth factor β (which also acts to inhibit angiogenesis,inflammation, and smooth muscle proliferation in most models, though itcan also provoke inflammation in non-inflamed tissue and delayendothelial regeneration). Nathan, et al., J Cell Bol 113:991-986(1991). Endothelial regeneration can be enhanced by basic or acidicfibroblast growth factor or by vascular endothelial growth factor, amongothers. Casscells, Circulation 91:2699-2702 (1995).

In summary, living human carotid atherosclerotic plaques exhibit thermalmicro-heterogeneity attributable mainly to macrophages at or near thelumen. These regions of increased temperature can be identified bythermistors and infrared thermography. If hot plaques are indeed at highrisk of thrombosis (or restenosis (Gertz, et al., Circulation 92:1-293(1995); Moreno, et al., Circulation 92:1-161 (1995)) or—in the case ofadventitial inflammation—of aneurysmal rupture, it may be possible todevelop catheter-based and noninvasive means of imaging and treatingthese potentially life-threatening lesions. These technologies mightalso be used to detect subepithelial clusters of inflammatory ormalignant cells in other organs by magnetic resonance imaging or byendoseopy, ophthalmoscopy, laparoscopy, artheroscopy, or transcranialimaging.

The present invention has been described in terms of particularembodiments found or proposed to comprise preferred modes for thepractice of the invention. It will be appreciated by those of skill inthe art that, in light of the present disclosure, numerous modificationsand changes can be made in the particular embodiments exemplifiedwithout departing from the intended scope of the invention. For example,while the present invention has been supported by examples in thebiomedical arts, the apparatus and methods of the invention may beequally well applied to the analysis of wall weaknesses of any vessel solong as such weaknesses exhibit or can be made to exhibit differentialheating. Thus, manmade vessels such as conduit, if heated externally maybe subjected to internal analysis using the apparatus and methods of theinvention. All such modifications are intended to be included within thescope of the appended claims.

1-56. (canceled)
 57. A system for differentiating different types ofplaque in a vessel and thereby detecting vulnerable plaque in vivo,comprising: a catheter having a proximal end and a distal end; one ormore thermal sensors at said distal end of said catheter; and a detectorcoupled to said proximal end of said catheter and in communication withsaid one or more thermal sensors, said detector being capable ofreceiving thermal information from said one or more thermal sensors anddifferentiating the different types of plaque based upon the thermalinformation received.
 58. The system of claim 57 further comprising anexpandable member at the distal end of the catheter.
 59. The system ofclaim 58 wherein the expandable member comprises a balloon.
 60. Thesystem of claim 59 wherein said thermal sensors comprise one or moreoptical fibers passing through said balloon.
 61. The system of claim 57wherein said thermal sensors comprise one or more optical fibers capableof transmitting optical radiation indicative of temperature.
 62. Thesystem of claim 57 wherein said detector is capable of determiningwhether the plaque exhibits an elevated temperature of up to 5° C. aboveat least one adjacent vessel wall site.
 62. The system of claim 57wherein said detector is capable of determining whether the plaqueexhibits an elevated temperature of between 0.4 to 4° C. above at leastone adjacent vessel wall site.
 63. The system of claim 57 wherein saiddetector is capable of determining whether the plaque exhibits anelevated temperature of at least 0.1° C. above at least one adjacentvessel wall site.
 64. The system of claim 62 wherein said detector iscapable of determining whether the plaque exhibits an elevatedtemperature of at least 1.5° C. above at least one adjacent vessel wallsite.